An updated review of teriflunomide's use in multiple sclerosis

Multiple sclerosis (MS), an autoimmune demyelinating disease, is the leading cause of nontraumatic disability in young adults [1]. In both developed and developing countries, the incidence and prevalence of MS are increasing [1]. MS has an estimated prevalence of 1 in 3000 people; about 2.8 million people are estimated to live with the disease globally [2,3]. In Europe and the Americas, prevalence rates are 133 and 112, respectively, per 100,000 people [1,2]. Most patients present with relapsing-remitting MS (RRMS), characterized by periods of acute ‘relapses’ caused by inflammatory lesions, followed by periods of decreased activity or ‘remissions.’ Many patients with RRMS eventually transition to secondary progressive MS, which involves gradual worsening or accumulation of symptoms [3].

Historically, key end points for most MS therapies have been annualized relapse rate (ARR), disability worsening and reduction of lesion numbers on magnetic resonance imaging (MRI) [3,4]. However, markers of acute focal inflammation do not correlate with long-term disability [5]. Although recent advances in disease-modifying therapies (DMT) have made it possible to effectively reduce the risk of focal inflammatory activity (and thus ARR), a need remains for improved therapeutic options that slow brain volume loss (BVL) and long-term disease progression. The lack of comprehensive head-to-head trials, real-world outcomes and patient-reported outcomes also drives a need for further research and understanding of MS treatments.

A review of the DMT teriflunomide (AUBAGIO^®, Sanofi Genzyme, MA, USA) published in 2017 summarized data from the core clinical development program and long-term extensions, real-world evidence and comparative effectiveness studies then available. This update to that review presents recently available evidence for teriflunomide, including direct comparisons with other DMTs in clinical studies, patient-reported outcomes, long-term effects on brain volume, evolving antiviral properties and outcomes for patients with MS treated with teriflunomide while infected with COVID-19.

Overview of currently available disease-modifying therapies

The first available DMTs for relapsing forms of MS were injectable interferons (IFNs: IFN-β-1a, IFN-β-1b, pegylated IFN-β-1a) [6–10] and glatiramer acetate (GA) [11], the earliest of which received US FDA approval in the 1990s (Table 1). In 2010 the first oral DMT, a sphingosine-1-phosphate (S1P) inhibitor (fingolimod), was approved to treat relapsing forms of MS [12]; approval of other S1P inhibitors followed in 2019 and 2020 [13,14]. Oral fumarates dimethyl fumarate (DMF), diroximel fumarate (DRF) and monomethyl fumarate (MMF) received approval in 2013, 2019 and 2020, respectively [15–17]. The purine antimetabolite cladribine was approved in 2019 [18]. Several monoclonal antibody (mAb) therapies have also been approved for use in MS. Natalizumab was the first mAb approved for this indication [19], followed by alemtuzumab [20], ocrelizumab [21] and ofatumumab [22].

The precise mechanisms by which all DMTs act in patients with MS are unknown, and mechanism descriptions are beyond the scope of this article, but all effect reductions in ARR, rates of disability progression and/or new lesions on MRI. Some (e.g., alemtuzumab) have also been shown to significantly reduce brain atrophy [20].

Teriflunomide

The oral DMT teriflunomide was first approved by the US FDA in 2012 to treat relapsing forms of MS (Table 1) [23]. Teriflunomide is dosed once daily at 7 or 14 mg in USA but is available only at 14 mg in other countries [4]. In the EU, teriflunomide use was recently approved in pediatric patients 10 years of age and above, with a recommended dose dependent on body weight (>40 kg: 14 mg once daily; ≤40 kg: 7 mg once daily; stable body weight above 40 kg: should be switched to 14 mg once daily) [24]. The clinical development program, comprising the Phase III, randomized clinical trials TEMSO, TOWER, TENERE and TOPIC, demonstrated significant improvements in ARR, rates of disability worsening and MRI outcomes for teriflunomide versus placebo in patients with relapsing MS [23]. Teriflunomide has a robust effect on neurodegenerative processes, as reflected in the preservation of brain volume [25,26] and reduction of disability progression [27]. Clinical trial extension data, Phase IV studies and real-world evidence have demonstrated long-term safety, efficacy and tolerability. Compared with placebo, teriflunomide is associated with increased incidence of hepatic events (primarily reversible alanine aminotransferase [ALT] increases), lymphopenia and neutropenia (≤15% reduction, with lymphocyte and neutrophil counts remaining in the normal range) [4].

Pharmacology

Chemistry & mechanism of action

The chemistry and proposed mechanism of action of teriflunomide were extensively covered in the 2017 publication of this review [4]. In brief, teriflunomide ([Z]-2-cyano-3-hydroxy-but-2-enoic acid-[4-trifluoromethylphenyl]-amide) is the principal active metabolite of leflunomide, and an open-ring malononitrile [4,23]. Leflunomide, the prodrug of teriflunomide, is rapidly converted in the intestinal mucosa or plasma, resulting in similar pharmacokinetics of the two agents [28]. Teriflunomide has a molecular mass of 270.2 Da, is practically insoluble in water (logP = 2.4), and has an acidic pKa of 5.48 [29].

Teriflunomide is a reversible, selective inhibitor of dihydroorotate dehydrogenase (DHODH), a rate-limiting mitochondrial enzyme required for de novo pyrimidine synthesis, which is required for expansion of antigen-activated (but not resting) lymphocytes [28,29]. Inhibition of de novo pyrimidine synthesis leads to a reduction in activated T and B cells available to enter the central nervous system (CNS). Because resting lymphocytes do not require de novo pyrimidine synthesis for proliferation, teriflunomide only interrupts proliferation of activated lymphocytes without affecting the normal homeostatic process for resting lymphocytes [30]. Teriflunomide inhibits the binding to DHODH of dihydroorotate (in an allosteric, noncompetitive manner) and of the electron acceptor ubiquinone (in a competitive manner) [28]. Teriflunomide is not a nucleotide analog [30]. The Ames test shows it is not DNA intercalating and does not affect cell viability [30].

In vitro and animal studies first suggested teriflunomide affects disease symptoms without inducing immunosuppression [30]. The effects of teriflunomide on size and function of human lymphocyte populations were explored in pooled analyses of the pivotal trials and separately in the Phase III, nonrandomized, open-label TERI-DYNAMIC study in patients with RRMS [31]. In TERI-DYNAMIC, lymphocyte and T helper type 1 cell (Th1) counts were reduced and CD4⁺/CD8⁺ T-cell ratios and induced regulatory T-cell (T_reg) counts were increased after teriflunomide treatment [31]. In pooled analyses, absolute lymphocyte counts declined over 24 weeks of treatment (mean, 1.89 [baseline] to 1.67 [week 24]), then remained stable. Mean counts generally remained within the normal range, but grade 1 and 2 lymphopenia occurred in 7.3 and 2.2% of patients, respectively [32]. The occurrence of grade 2 lymphopenia was associated with decreased mean lymphocyte counts from baseline through week 48, after which lymphocyte counts stabilized [32]. Most cases of grade 1 or 2 lymphopenia occurred during the first year of treatment; fewer cases were reported after year 3, although the incidence of grade 1 lymphopenia rose slightly during years 6–8 [32].

Lymphocyte and Th1 counts are reduced with teriflunomide, CD4⁺/CD8⁺ T-cell ratios and T_reg counts are increased, and CD4⁺ clonal diversity is reduced. In TERI-DYNAMIC, following 24 weeks of treatment, total lymphocyte counts remained within the clinically normal range, although reductions from baseline were observed in absolute lymphocyte counts (-284.94; p < 0.001) and percentages of lymphocytes (-3.05%; p < 0.05), CD19⁺ B cells (-2.0%; p = 0.001) and CD8⁺ cells (-1.0%; p < 0.01), and increases occurred in CD4⁺ populations (1.6%; p < 0.01) and CD4⁺/CD8⁺ ratios [31]. In an analysis of CD4⁺ T-cell subpopulations, a selective effect on induced T_reg, natural T_reg and Th1 cells was seen, suggesting a shift in T-cell populations from proinflammatory to regulatory and potentially anti-inflammatory T cells [31]. Further, in vitro exposure to teriflunomide significantly reduced T-cell production of proinflammatory cytokines. In vitro and ex vivo findings from TERI-DYNAMIC supported a reversible effect of teriflunomide, and study results were consistent with observations from TEMSO and TOWER [4].

In support of an immunomodulatory role, patients receiving teriflunomide are not at increased risk of malignancy or serious infection. Most teriflunomide-treated patients achieved seroprotection to both neoantigens and recall antigens in rabies and influenza vaccine studies, respectively. In a study using the rabies vaccine, all vaccinated patients achieved antibody titers >0.5 IU/ml and teriflunomide did not adversely affect the cellular memory response to recall antigens [33]. After receiving the 2011/2012 seasonal influenza vaccine in the Phase II TERIVA study, patients generally had an effective immune response, with >90% of patients achieving antibody titers ≥40 (considered protective immunity) for H1N1 and influenza B and 77–90% achieving titers ≥40 for H3N2 [34].

Pharmacodynamics, pharmacokinetics & metabolism

The pharmacokinetic properties of teriflunomide were summarized previously [4]. Briefly, teriflunomide exhibits 100% oral bioavailability and dose-dependent systemic exposure; pharmacokinetic characteristics are not significantly affected by food intake, mild or moderate hepatic impairment or severe renal impairment [23,28]. However, clearance rate is 23% lower in female than in male patients and teriflunomide is contraindicated in patients with severe hepatic impairment [23].

Peak plasma levels occur 1–4 h after dosing, and elimination half-life is approximately 18–19 days for both dose levels. Elimination occurs primarily through direct biliary excretion of the unchanged drug (37.5% in the feces) and renal excretion (22.6% via urine) [23]. Teriflunomide undergoes extensive enterohepatic recirculation, resulting in very slow total plasma clearance [24]. Steady state is reached after approximately 3 months of treatment. However, this recycling also means cholestyramine or activated charcoal may be used to rapidly eliminate teriflunomide by >98% after 11 days [23]. Plasma protein binding is >99%, but volume of distribution is only 11 l [23]. Data suggest teriflunomide inhibits CYP2C8 and is a weak CYP1A2 inducer but does not affect pharmacokinetics of other CYP substrates, including bupropion (CYP2B6), midazolam (CYP3A4), S-warfarin (CYP2C9), omeprazole (CYP2C19) and metoprolol (CYP2D6) [23].

A recent study using an experimental autoimmune encephalomyelitis (EAE) mouse model and fluorine-19 MRI detected teriflunomide in the blood (10.68–40.91 μg/g), brain (0.23–9.32 μg/g) and cerebrospinal fluid (0.74–2.68 μg/g) of healthy mice and EAE mice with brain lesions treated for over 13 days [35]. This finding supports a previous animal study that detected biologically relevant concentrations of teriflunomide in brain and spinal cord, suggesting teriflunomide may have local activity in the CNS [36].

Clinical efficacy

Clinical development program (Phase II & III studies)

A Phase II study (NCT01487096) [37,38] and the Phase III TEMSO (NCT00134563) [27], TOWER (NCT00751881) [39], TOPIC (NCT00622700) [40] and TENERE (NCT00883337) [41] studies all demonstrated teriflunomide efficacy in adults with MS. Key outcomes of these trials and their extensions were described previously (Table 2) [4]. In these studies, patients treated with teriflunomide showed improvements over placebo in ARR, disability worsening and MRI outcomes, which were sustained in long-term extensions.

The TERIKIDS study evaluated time to first relapse and MRI outcomes with teriflunomide in 166 children (10–17 years old) with relapsing MS. The study, which has been presented in abstract form [42,43], included 96 weeks of double-blind, randomized, placebo-controlled treatment with 14 mg adult equivalent of teriflunomide or placebo, followed by an open-label extension with up to 192 weeks of teriflunomide. In addition to the primary end point of time to first clinical relapse, the study also included a prespecified sensitivity analysis of time to first relapse or high MRI activity. While teriflunomide reduced the risk of clinical relapse by 34% compared with placebo (median time to relapse, 75.3 vs 39.1 weeks, respectively), the difference was not statistically significant (p = 0.29). This is possibly because more patients than anticipated switched from the double-blind to open-label periods due to high MRI activity, which is consistent with clinical practice where relapses and MRI findings are routinely integrated in the clinical management of pediatric MS patients, including treatment selection. Switches were more frequent and occurred earlier in the placebo group (teriflunomide, 13%; placebo, 26%), leading to reduced study power and potentially biasing results against treatment efficacy. The prespecified sensitivity analysis detected statistically significantly longer median times to clinical relapse or switch due to high MRI activity with teriflunomide (72.1 weeks) compared with placebo (37.0 weeks; 43% relative risk reduction; p = 0.04). Statistically significant reductions were also observed in the adjusted number of T1 gadolinium-enhancing (Gd+) lesions per MRI scan (teriflunomide, 1.9; placebo, 7.5; 75% relative reduction; p < 0.0001) and T2 lesions (4.7 vs 10.5, respectively; 55% relative reduction; p = 0.0006) and least-squares mean change from baseline in T2 lesion volume at weeks 24 (0.08 vs 0.15; p = 0.046), 72 (0.07 vs 0.20; p = 0.005) and 96 (0.07 vs 0.20; p = 0.01) [42].

Comparative effectiveness

Teriflunomide has been used as an active comparator in recent Phase III studies (Table 3). The previous review described the TENERE study and extension, which compared teriflunomide 7 and 14 mg with IFN-β-1a 44 μg [4,41]. A 2018 analysis of patient-reported outcomes from the 96-week TENERE extension described statistically significant (p < 0.01) improvements in patient satisfaction related to side effects and convenience after switching from IFN-β-1a to teriflunomide [44]. The OPTIMUM study randomized patients with relapsing MS to ponesimod 20 mg once daily (QD) or teriflunomide 14 mg QD. At week 108, the ponesimod group had a significantly lower ARR compared with teriflunomide (0.202 vs 0.290; p = 0.0003) and significantly improved fatigue scores [45]. ASCLEPIOS I and II compared teriflunomide 14 mg QD with ofatumumab 20 mg every 4 weeks, reporting lower ARRs, fewer Gd+ T1 and new/enlarging T2 lesions, and lower rates of disability worsening with ofatumumab versus teriflunomide, but similar rates of clinical disability improvement and BVL reduction [46].

An analysis using data from pivotal studies of teriflunomide (TEMSO and TOWER), DMF (DEFINE and CONFIRM) and fingolimod (FREEDOMS and FREEDOMS II) calculated numbers needed to treat (NNT) to prevent relapses or disability worsening. NNTs were generally comparable for the prevention of any relapse (5.6–5.9 vs 5.3–5.6 vs 4.5–5.3, respectively), relapses leading to hospitalization (12.2–20.0 vs 50.0–58.8 vs 9.1–83.3) or requiring intravenous corticosteroids (6.3–6.9 vs 6.3–6.7 vs 4.8–6.9), and disability worsening (13.7–17.1 vs 10.8–30.2 vs 15.3–23.5). However, differences in study design and patient populations should be considered when evaluating cross-trial comparisons [47].

Real-world evidence

Observational studies have assessed real-world outcomes for patients with relapsing forms of MS treated with teriflunomide. The Phase IV Teri-PRO study was described in the previous review [4], but additional results have since been reported [48,49]. Teri-PRO (N = 1000) used patient-reported outcomes to assess treatment satisfaction and changes in disability, cognition and quality of life over 48 weeks. Such assessments are important to help clinicians understand the impact of treatment on patients' daily life, which may not be captured in traditional clinical study end points. Patients reported high overall treatment satisfaction on the Treatment Satisfaction Questionnaire for Medication scale (TSQM; mean score, 68.2) [49]. Patients who had switched from another DMT to teriflunomide reported significantly improved satisfaction (p < 0.001) at week 48 compared with baseline, both overall and across TSQM subscales of effectiveness, convenience and side effects (Figures 1 & 2) [48]. In the overall population, the highest scores were in the side effects (84.1) and convenience (90.4) TSQM subdomains. These subdomains corresponded with the most common reasons for switching to teriflunomide (i.e., convenience of an oral formula and safety concerns around other DMTs) [49]. Disability scores remained stable throughout the study, including patient-reported disability, as measured by the Patient-Determined Disease Steps (PDDS) scale, and Expanded Disability Status Scale (EDSS) scores [49]. Quality-of-life scores measured using the Multiple Sclerosis International Quality of Life (MusiQoL) significantly improved from baseline to week 48 (mean [95% CI], 67.7 [66.7–68.6] to 69.2 [68.1–70.2]; p = 0.003), with most subscale scores remaining stable or improving over time. Similarly, scores remained stable for the Stern Leisure Activity Scale (mean [95% CI], 7.30 [7.16–7.44] to 7.40 [7.24–7.56]) and two scales measuring cognition. The annualized treated relapse rate was 0.20 [49].

The observational TACO study (N = 47) assessed patient-reported and clinical outcomes after 24 months of teriflunomide treatment [50]. The ARR remained low at 24 months (0.14; 95% CI, 0.07–0.25), EDSS scores remained stable compared with baseline and 80.9% of patients did not experience disability worsening. Assessments of quality of life via the Multiple Sclerosis Impact Scale (MSIS-29) suggested stable physical and psychologic status, with mean (95% CI) changes from baseline to month 24 of 0.0 (-5.4 to 5.5; p = 0.986) and -3.6 (-8.9 to 1.6; p = 0.374), respectively. Treatment satisfaction, effectiveness, side effects, and convenience scores improved, with mean (95% CI) changes from baseline to month 24 of 15.4 (-1.2 to 32.1), 4.5 (-10.4 to 19.4), 22.8 (1.2–44.4), and 21.2 (10.3–32.2), respectively. Cognition, anxiety/depression, and fatigue scores remained relatively stable over 24 months, with small or no changes from baseline [50].

TAURUS-MS was a prospective observational study of 1128 patients with RRMS, for whom mean ARR decreased from 0.87 in the 2 years before study entry to 0.35 during the 2-year observational period (p ≤ 0.001) [51]. EDSS and fatigue scores remained stable throughout treatment. TSQM scores improved from baseline to 24 months among patients who received another DMT before study entry (global satisfaction, 15.3-point improvement; effectiveness, 8.1; convenience, 17.0; p < 0.001 for all).

Patient-reported outcomes were also evaluated in the observational Teri-FAST (N = 210) [52], Teri-REAL (N = 100) [53] and Teri-LIFE (N = 200) [54] studies. Teri-FAST assessed fatigue (via EMIF-SEP, a version of the Modified Fatigue Impact Scale [MFIS]), depression (Beck Depression Inventory [BDI]) and health-related quality of life (Two-Life Scale [TLS-QoL 10]). Between baseline and year 2, patients reported stable fatigue (mean change, -1.54; 95% CI -4.02 to 0.94), depression (-0.6; -1.5 to 0.3) and health-related quality of life (-0.3; -0.8 to 0.1) [52]. Similarly, physical and psychologic domains of the MSIS-29 remained stable throughout Teri-REAL (mean ± SD changes from baseline to month 12, 2.4 ± 16.5 [p = 0.265] and 0.0 ± 20.7 [p = 0.990], respectively) [53]. Treatment satisfaction measured using TSQM remained steady or improved (global satisfaction, 0.9 ± 3.4 [p = 0.075]; convenience, 1.1 ± 2.6 [p = 0.006]; effectiveness, 0.5 ± 4.6 [p = 0.480]). Teri-LIFE reported relatively stable physical and mental quality of life measured via the Short Form-36 (SF-36), with mean (95% CI) 24-month changes from baseline of -1.5 (-2.8 to -0.2; p = 0.0038) and 1.6 (-0.2 to 3.5; p = 0.115), respectively. In Teri-LIFE the on-treatment ARR was 0.17 (95% CI, 0.13–0.23) [54].

Safety & tolerability

The safety and tolerability profile of teriflunomide is well established and consistent across studies, including in clinical trial and real-world settings. The previous review summarized the overall safety data for teriflunomide, including results from a pooled analysis of Phase II and Phase III pivotal studies. In that analysis, adverse events (AEs) were similar between the core studies and the study extensions, with no new or unexpected events occurring during longer-term use in extension studies [4,55].

Real-world evidence supports the safety profile seen in clinical trials. About 82% of patients in Teri-PRO experienced AEs, most of which were of mild or moderate severity and included hair thinning, diarrhea, nausea, headache, urinary tract infection and ALT increase (Table 4) [48,49]. AEs led to treatment discontinuation for 10.9% of patients. MS relapse was the only serious AE reported for >1% of patients, and diarrhea and MS relapse were the only AEs leading to discontinuation in >1% of patients. In TACO, 21.8% of patients experienced treatment-related AEs, most commonly hair thinning (10.9%) and diarrhea (9.1%), and none reported serious AEs [50]. TAURUS-MS reported AEs for 35.8% of patients, the most frequent of which were diarrhea, MS relapse, hair thinning and viral upper respiratory tract infection (Table 5). Serious AEs in TAURUS-MS included one death due to bronchopulmonary aspergillosis that was assessed by the investigator as related to teriflunomide, although confounding factors may have played a role [51].

Recent publications of comparative studies with teriflunomide now permit safety comparisons between teriflunomide and other treatments. A pooled analysis of ASCLEPIOS I and II reported the rates of AEs for teriflunomide and ofatumumab were 84.2 and 83.6%, respectively, and rates of serious AEs were 7.9 and 9.1%, respectively [46]. In that analysis, infections and serious infections were reported for 52.7 and 1.8% of patients who received teriflunomide and 51.6 and 2.5% who received ofatumumab. Injection-related systemic reactions occurred in 15.0% of patients in the teriflunomide group who received placebo injections and 20.2% in the ofatumumab group. One of the two (0.2%) grade 3 injection-related systemic reactions in the ofatumumab group led to treatment discontinuation. Malignancies were reported for four (0.4%) patients receiving teriflunomide and five (0.5%) receiving ofatumumab [46].

In TERIKIDS, children receiving teriflunomide had higher infection rates (66.1%; 1.38 events/person-year) compared with those receiving placebo (45.6%; 0.99 events/person-year) [42]. However, rates of any AEs and serious AEs were similar between the teriflunomide and placebo groups (any AEs, 88.1 vs 82.5%, respectively; serious AEs, 11.0 vs 10.5%). AEs occurring with high frequency with teriflunomide (≥5% more than placebo) included nasopharyngitis, hair thinning, upper respiratory tract infection, paresthesia, abdominal pain and increased blood creatine phosphokinase. Two teriflunomide-treated patients experienced acute pancreatitis during the double-blind period, leading to treatment discontinuation and one of these events led to hospitalization and required corrective treatment [24,42]. No deaths were observed in the placebo or teriflunomide groups. Overall, the beneficial effects of teriflunomide were similar to those seen in adults, with a manageable safety profile.

To date, teriflunomide has not been associated with QT prolongation [23], but the US label does have a boxed warning regarding the risk of hepatotoxicity and embryofetal toxicity [23]. Given these risks, liver monitoring should be done within 6 months before treatment initiation and monthly for 6 months after treatment initiation. Teriflunomide is associated with a 10% reduction in platelet count and a 15% reduction in white blood cell count (primarily neutrophils and lymphocytes) during the first 6 weeks, which remained low throughout treatment [23].

Teriflunomide is contraindicated in pregnancy based on data from preclinical animal studies, but data in human pregnancy are limited. Patients not wishing to become pregnant should use reliable contraception. Patients wishing to become pregnant may undergo an 11-day accelerated elimination program [23]. The teriflunomide clinical development program required patients to use reliable contraception and prohibited pregnant women from participating. The prescribing information for teriflunomide also recommends that women of childbearing potential use reliable contraception during treatment and during an accelerated elimination procedure (if treatment is discontinued). Despite these precautions, more than 400 pregnancies (222 with known outcomes) were reported by December 2017 in clinical trials and real-world use [56]. The previous review described the 70 pregnancies reported for women in the clinical development program [4]. In this update, all pregnancies with known outcomes are described in Table 6.

The only major birth defect associated with teriflunomide exposure was a case of ureteropyeloectasia. Five minor birth defects were reported in live births or stillbirths (congenital hydrocephalus, ventricular septal defect, malformation of right foot valgus, congenital pes planus, congenital hip dysplasia) [56,57]. In the one major and three minor birth defects in infants born to women receiving teriflunomide, teriflunomide exposure occurred only during the first trimester [56]. In a study of 48 pregnancies in female partners of men treated with teriflunomide, no detectable embryofetal toxicity signal was observed [57]. The rates of major and minor birth defects and spontaneous abortions in the two analyses were considered comparable to, or below, those in the general population [56,57]. These findings are encouraging for patients who unknowingly take teriflunomide in the early stages of pregnancy, but further data are needed before conclusions can be drawn regarding treatment safety in pregnancy.

A population-based analysis of pregnancy data from the Danish Multiple Sclerosis Registry described 31 pregnancies in 13 women receiving teriflunomide and 18 partners of teriflunomide-treated men. Female patients with MS had 11 elective abortions and two live births, neither with congenital malformations. All 18 pregnancies in female partners of treated men led to live births, with one congenital malformation reported (plagiocephaly). Compared with controls from the general population, teriflunomide-exposed pregnancies were associated with 22% reduced odds of any AE, although the association did not reach statistical significance (95% CI, 0.16–3.72; p = 0.753) [58].

Antiviral effects

Some evidence suggests MS results from a combination of genetic and environmental factors [59], and exposure to certain viruses may play a critical role in the development of MS and occurrence of relapses [60,61]. Primary exposure to, and reactivation of, some viruses may trigger or worsen disease progression and increase exacerbation risk [62]. In addition, the presence of certain viruses, such as John Cunningham virus (JCV), increases the risk of serious complications (e.g., progressive multifocal leukoencephalopathy [PML]) [63]. DMTs have varying effects on immunomodulation or immunosuppression, and long-term use of some DMTs may further increase patients' susceptibility to viral infection [64].

Preclinical evidence suggests teriflunomide reduces production or viral loads of herpes simplex virus-1 and the BK polyomavirus, which is closely related to JCV [65]. In vitro studies also suggest teriflunomide may inhibit JCV infection and spread in a dose-dependent manner [66]. No medically confirmed cases of PML matching the American Academy of Neurology (AAN) criteria have been attributed to teriflunomide to date, with over 435,246 patient-years of teriflunomide exposure in MS [67,68], whereas PML has been reported in patients treated with DMF, fingolimod and natalizumab [64].

The potential antiviral properties of teriflunomide were further supported by an ex vivo study that suggested teriflunomide inhibits abnormal T-cell proliferation associated with human T-lymphotrophic virus-1 (HTLV-1) infection, which causes HTLV-1–associated myelopathy/tropical spastic paraparesis, a chronic inflammatory CNS disease [69].

Based on in vitro studies suggesting teriflunomide may have antiviral activity against Epstein-Barr virus (EBV), a clinical study was conducted in 19 patients receiving teriflunomide 14 mg to treat RRMS [70]. The study used reference cohorts comprising 157 patients with MS (untreated or receiving another DMT) who had salivary samples assessed for the presence of EBV DNA. The proportions of patients with salivary EBV DNA or EBV shedding were numerically lower for teriflunomide versus the reference cohorts, and significantly fewer salivary samples from teriflunomide-treated patients were positive for EBV DNA or EBV shedding. Of the 11 teriflunomide-treated patients positive for EBV DNA, two patients accounted for the majority of EBV shedding [70]. The study provided preliminary evidence suggesting the possibility teriflunomide may have antiviral effects on EBV load. A separate study in 30 patients with MS reported reductions in EBV nuclear antigen-1 and viral capsid antigen titers compared with healthy controls during the first 12 months of teriflunomide treatment [71]. Patients with the greatest reductions from baseline had significantly less cortical and gray matter BVL.

As described above, studies of rabies and influenza vaccines in patients with MS suggest most teriflunomide-treated patients achieved seroprotection to neoantigens and recall antigens, respectively [33,34].

Experience of COVID-19 in teriflunomide-treated patients

This article was prepared during the global outbreak of the 2019 novel coronavirus (SARS-CoV-2) that causes COVID-19. Given the varying effects of DMTs on immunomodulation and immunosuppression, concerns have arisen that DMTs might increase patient risk of SARS-CoV-2 infection, impair the immune response, or contribute to poor outcomes [72]. The influence (if any) of teriflunomide treatment on the course of COVID-19 has therefore been of concern to physicians and patients. One case series described five patients with MS treated with teriflunomide who were infected with SARS-CoV-2 [72]. Patients included three men and two women aged 38–79 years with EDSS scores of 0–6 who had received teriflunomide 14 mg/day for up to 4 years. Three had comorbidities, and two had a body mass index >25 kg/m² (28.5 and 29.9 kg/m²). All five continued a stable teriflunomide dose during infection and had self-limiting infection that did not require hospitalization or lead to MS relapse. In all cases, symptoms resolved ≤39 days after COVID-19 diagnosis [72].

A separate case series reported that six patients with MS continued teriflunomide treatment without experiencing MS relapse during symptomatic COVID-19 infection [73]. Patients included four women and two men aged 34–57 years with EDSS scores of 1–4.5 who had been receiving teriflunomide for 0.5–5 years. None had relevant comorbidities or required hospitalization during COVID-19 infection, and all recovered without receiving specific treatment. One patient reported diplopia, which was interpreted by the treating physician as a pseudorelapse [73].

In a separate report, a 42-year-old man receiving teriflunomide for RRMS was hospitalized for 4 days and treated with high-dose methylprednisolone for neurologic symptoms presumed to indicate MS relapse. The day after discharge, neurologic symptoms deteriorated and the patient developed fever, hypotension, tachycardia and increased serum acute phase reactant (APR) levels, leading to rehospitalization and COVID-19 diagnosis. The patient received symptomatic treatment (no supplemental oxygen) and was discharged 1 week later, following resolution of fever and reduction of APR levels [74]. The authors did not report whether teriflunomide was continued during the second hospitalization.

In a 62-year-old woman with RRMS (EDSS score = 6), teriflunomide was discontinued during a 6-day hospitalization for COVID-19–related pneumonia, but plasma levels of teriflunomide remained >10 mg/l at discharge. Based on analysis of CD4⁺ and CD8⁺ T cells before and during infection, the authors suggested teriflunomide may prevent T-cell hyperactivation in COVID-19–related pneumonia [75].

Teriflunomide was also suspended during hospitalization for COVID-19 in a 58-year-old woman with RRMS. Despite hospitalization, this patient developed only slight dyspnea and had adequate immunoglobulin G (IgG) antibody production by the third week of infection for both antinucleocapsid (≥1.322) and anti–spike protein S1 receptor binding domain (S1RBD; ≥1.229) [76].

One fatality has been reported of a 55-year-old woman with advanced secondary progressive MS who interrupted teriflunomide treatment at the time of COVID-19 diagnosis. The patient had an EDSS score of 7.5 and a comorbid diagnosis of myotonic dystrophy. The patient's condition deteriorated despite being placed on supplemental oxygen, and she died 4 days after hospitalization [77].

The consistency among these case reports suggests teriflunomide might not negatively affect the disease course of COVID-19.

Effects on brain volume

BVL is associated with long-term accumulation of cognitive and physical disability associated with MS, which affects patients' daily function and quality of life [25]. Additionally, disability progression occurs independent of acute focal inflammation [5] and may result from chronic smoldering disease [78]. It is therefore important that MS treatments limit BVL in addition to acute manifestations such as annualized relapses and lesion volumes.

In vitro studies have evaluated the neuroprotective effects of teriflunomide in the CNS. In a study by Woodworth et al. [79], teriflunomide directly affected the functions of activated microglia and astrocytes. Compared with microglia treated with dimethyl sulfoxide (DMSO) control, cells from mice treated with teriflunomide exhibited suppressed proinflammatory cytokine production, reduced gene expression of proinflammatory cytokines and increased gene expression and production of interleukin 10. Additionally, stimulated astrocytes were protected against H₂O₂-induced cytotoxicity [79].

Analyses of MRI data from TEMSO and TOPIC suggested teriflunomide significantly affects BVL and focal inflammation compared with placebo (Table 7). In the TEMSO core and extension study, patients with the least BVL were significantly less likely to experience disability worsening over 7 years, and BVL was predictive of long-term disability worsening at year 7 [80]. Moreover, BVL from baseline to year 2 was found to explain the greatest proportion of treatment effect of teriflunomide 14 mg on 12-week confirmed disability worsening (51.3%) compared with relapses and new or enlarging T2-weighted lesions (38.5 and 30.8%, respectively). Teriflunomide 14 mg was associated with statistically significantly smaller changes in brain volume compared with placebo in patients regardless of whether or not they had 12- or 24-week confirmed disability worsening (Figure 3) [25]. Teriflunomide was also associated with improved cognitive performance from baseline to year 2 versus placebo (p = 0.0146), and a post hoc analysis suggested the treatment effects on BVL (rather than effects on lesions or ARR) explained 44.2% of the treatment effect of teriflunomide on cognition [81].

In TOPIC, teriflunomide 14 mg was associated with significantly smaller changes in cortical gray matter volume versus placebo at months 6–24 [26]. Also, greater magnitude of cortical gray matter BVL was associated with a higher risk of conversion to clinically definite MS [26]. ASCLEPIOS I and II reported similar annual rates of BVL between teriflunomide and ofatumumab, based on assessments of percent brain volume change from baseline performed at 12 and 24 months [46]. In comparison, the real-world Teri-RADAR study described significantly reduced annualized percent whole BVL at 24 months compared with DMF (median change, -0.1 vs -0.5; p = 0.0212) [82]. The consistency of these data suggest teriflunomide may reduce BVL in patients with relapsing forms of MS, which is corroborated in the consistent effects seen in reduction of disability worsening and improvement of quality-of-life measures. Future efforts should explore whether these observations are potentially related to teriflunomide's effect on diffuse and/or chronic smoldering inflammation [83].

Regulatory affairs

Teriflunomide is approved in more than 80 countries as of January 2021. US approval for the treatment of relapsing forms of MS includes clinically isolated syndrome, RRMS and active secondary progressive disease, in adults. Both 7- and 14-mg doses are approved in the US, whereas approval in other countries is only for the 14-mg dose. In the EU, teriflunomide is indicated for the treatment of adults with RRMS.

Conclusion

Clinical trials of teriflunomide treatment lasting up to 9 years in adults with relapsing forms of MS or with a first clinical episode suggestive of MS consistently demonstrated lasting improvements in disease measures such as ARR, disability worsening and MRI outcomes. Data from the clinical development program have now been supplemented by real-world evidence and comparisons with other DMTs in patients with relapsing forms of MS. Treatment safety and tolerability in these studies has been consistent with that seen in the clinical development program, further supporting the long-term safety and tolerability of teriflunomide. The pediatric TERIKIDS recently reported efficacy and safety results similar to those seen in adult studies, in which time to relapse and MRI activity were reduced with teriflunomide versus placebo with no unexpected safety signals.

Consistently, teriflunomide has demonstrated a significant impact on disability progression and brain atrophy across clinical trials and real-world studies starting early in the disease course. This suggests teriflunomide targets the neurodegenerative process in addition to the well-characterized effect on focal inflammation.

Patient-reported outcomes from Teri-PRO and other observational studies suggest high overall patient satisfaction with teriflunomide, both in patients new to DMTs and in those who switch from another DMT. Patients previously treated with other DMTs report particularly high treatment satisfaction related to convenience and side effects.

Preliminary evidence suggests teriflunomide supports an immune antiviral response, in contrast to other DMTs that may increase susceptibility for viral infections. Initial case reports of patients infected with COVID-19 also suggest teriflunomide does not negatively affect the disease course.

Taken together, these results from recent clinical trial and real-world analyses add to the established safety and efficacy profiles for teriflunomide, further supporting its use in treating relapsing forms of MS.

Future perspective

DMTs have been shown to reduce the risk of focal inflammation, but do not necessarily affect long-term disease progression or patient disability. For many patients, disease continues to progress despite the use of DMTs to control relapses and lesions. Therapeutic options are needed that can address the chronic smoldering inflammation that remains ongoing during remissions, which plays a role in progression of the disease. Given the potential for such therapies to improve quality of life and long-term outcomes for patients with relapsing forms of MS, research may increasingly focus on the pathological drivers of chronic smoldering inflammation in MS and the ability of current or new DMTs to target this underlying disease activity.